Congenital human cytomegalovirus (HCMV) infection represents an important cause of neurological damage in children and is the leading cause of non-familial hearing loss in the US. Little is understood about the pathogenesis of this infection because suitable models of central nervous system (CNS) infection are lacking. We have developed a murine model of congenital HCMV infection which recapitulates many of the histopathological and neurodevelopmental abnormalities described in congenital HCMV infections, including hearing loss in surviving mice. In contrast to earlier models, newborn mice injected peripherally with murine CMV develop viremia and subsequently, encephalitis. Because newborn mice are neurodevelopmentally and immunologically equivalent to late 2nd trimester human fetuses, this model has also enabled us to study resolution of this virus infection in a developing animal. In this proposal we will study aspects of the CNS infection in these animals including mechanisms of neuroinvasion, the contribution of innate immune responses in clearance of the virus from the CNS, and the interplay between innate immunity and adaptive immune responses in clearance of virus from the CNS. Lastly, the contribution of both innate and adaptive immunity in persistent CNS infection in adult mice infected as newborns will be studied. We anticipate that parameters of the pathogenesis of CMV infection in the developing CNS will be identified from these studies. Furthermore, we believe that these findings can be translated directly into more focused studies in humans that could lead to new approaches for prevention and treatment of this important infection. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus infection in the developing fetus is a major cause of brain disease in infants and children. Currently no vaccines or treatment exist for this infection that is transmitted from the mother to the fetus. This project will utilize a highly related mouse virus and a mouse model of this disease to understand the characteristics of this infection that result in brain infection and the immune responses that limit virus growth and damage to the developing brain.